Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis / Palomo-Irigoyen, M.; Perez-Andres, E.; Iruarrizaga-Lejarreta, M.; Barreira-Manrique, A.; Tamayo-Caro, M.; Vila-Vecilla, L.; Moreno-Cugnon, L.; Beitia, N.; Medrano, D.; Fernandez-Ramos, D.; Lozano, J. J.; Okawa, S.; Lavin, J. L.; Martin-Martin, N.; Sutherland, J. D.; de Juan, V. G.; Gonzalez-Lopez, M.; Macias-Camara, N.; Mosen-Ansorena, D.; Laraba, L.; Oliver Hanemann, C.; Ercolano, E.; Parkinson, D. B.; Schultz, C. W.; Arauzo-Bravo, M. J.; Ascension, A. M.; Gerovska, D.; Iribar, H.; Izeta, A.; Pytel, P.; Krastel, P.; Provenzani, A.; Seneci, P.; Carrasco, R. D.; Sol, A. D.; Martinez-Chantar, M. L.; Barrio, R.; Serra, E.; Lazaro, C.; Flanagan, A. M.; Gorospe, M.; Ratner, N.; Aransay, A. M.; Carracedo, A.; Varela-Rey, M.; Woodhoo, A.. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 130:7(2020), pp. 3848-3864. [10.1172/JCI130379]

HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis

Provenzani A.;
2020-01-01

Abstract

Cancer cells can develop a strong addiction to discrete molecular regulators, which control the aberrant gene expression programs that drive and maintain the cancer phenotype. Here, we report the identification of the RNA-binding protein HuR/ ELAVL1 as a central oncogenic driver for malignant peripheral nerve sheath tumors (MPNSTs), which are highly aggressive sarcomas that originate from cells of the Schwann cell lineage. HuR was found to be highly elevated and bound to a multitude of cancer-associated transcripts in human MPNST samples. Accordingly, genetic and pharmacological inhibition of HuR had potent cytostatic and cytotoxic effects on tumor growth, and strongly suppressed metastatic capacity in vivo. Importantly, we linked the profound tumorigenic function of HuR to its ability to simultaneously regulate multiple essential oncogenic pathways in MPNST cells, including the Wnt/β-catenin, YAP/TAZ, RB/E2F, and BET pathways, which converge on key transcriptional networks. Given the exceptional dependency of MPNST cells on HuR for survival, proliferation, and dissemination, we propose that HuR represents a promising therapeutic target for MPNST treatment.
2020
7
Palomo-Irigoyen, M.; Perez-Andres, E.; Iruarrizaga-Lejarreta, M.; Barreira-Manrique, A.; Tamayo-Caro, M.; Vila-Vecilla, L.; Moreno-Cugnon, L.; Beitia, N.; Medrano, D.; Fernandez-Ramos, D.; Lozano, J. J.; Okawa, S.; Lavin, J. L.; Martin-Martin, N.; Sutherland, J. D.; de Juan, V. G.; Gonzalez-Lopez, M.; Macias-Camara, N.; Mosen-Ansorena, D.; Laraba, L.; Oliver Hanemann, C.; Ercolano, E.; Parkinson, D. B.; Schultz, C. W.; Arauzo-Bravo, M. J.; Ascension, A. M.; Gerovska, D.; Iribar, H.; Izeta, A.; Pytel, P.; Krastel, P.; Provenzani, A.; Seneci, P.; Carrasco, R. D.; Sol, A. D.; Martinez-Chantar, M. L.; Barrio, R.; Serra, E.; Lazaro, C.; Flanagan, A. M.; Gorospe, M.; Ratner, N.; Aransay, A. M.; Carracedo, A.; Varela-Rey, M.; Woodhoo, A.
HuR/ELAVL1 drives malignant peripheral nerve sheath tumor growth and metastasis / Palomo-Irigoyen, M.; Perez-Andres, E.; Iruarrizaga-Lejarreta, M.; Barreira-Manrique, A.; Tamayo-Caro, M.; Vila-Vecilla, L.; Moreno-Cugnon, L.; Beitia, N.; Medrano, D.; Fernandez-Ramos, D.; Lozano, J. J.; Okawa, S.; Lavin, J. L.; Martin-Martin, N.; Sutherland, J. D.; de Juan, V. G.; Gonzalez-Lopez, M.; Macias-Camara, N.; Mosen-Ansorena, D.; Laraba, L.; Oliver Hanemann, C.; Ercolano, E.; Parkinson, D. B.; Schultz, C. W.; Arauzo-Bravo, M. J.; Ascension, A. M.; Gerovska, D.; Iribar, H.; Izeta, A.; Pytel, P.; Krastel, P.; Provenzani, A.; Seneci, P.; Carrasco, R. D.; Sol, A. D.; Martinez-Chantar, M. L.; Barrio, R.; Serra, E.; Lazaro, C.; Flanagan, A. M.; Gorospe, M.; Ratner, N.; Aransay, A. M.; Carracedo, A.; Varela-Rey, M.; Woodhoo, A.. - In: THE JOURNAL OF CLINICAL INVESTIGATION. - ISSN 0021-9738. - 130:7(2020), pp. 3848-3864. [10.1172/JCI130379]
File in questo prodotto:
File Dimensione Formato  
JNCI FINAL 1st submission.pdf

accesso aperto

Descrizione: Prima sottomissione Articolo
Tipologia: Pre-print non referato (Non-refereed preprint)
Licenza: Tutti i diritti riservati (All rights reserved)
Dimensione 1.02 MB
Formato Adobe PDF
1.02 MB Adobe PDF Visualizza/Apri
130379.3-20201218131649-covered-e0fd13ba177f913fd3156f593ead4cfd.compressed.pdf

accesso aperto

Tipologia: Versione editoriale (Publisher’s layout)
Licenza: Creative commons
Dimensione 4.28 MB
Formato Adobe PDF
4.28 MB Adobe PDF Visualizza/Apri

I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione

Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11572/285314
Citazioni
  • ???jsp.display-item.citation.pmc??? 15
  • Scopus 35
  • ???jsp.display-item.citation.isi??? 37
social impact